EP2186810A1 - Dérivés de poly-hétéroaryle pour le traitement de cancer - Google Patents

Dérivés de poly-hétéroaryle pour le traitement de cancer Download PDF

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Publication number
EP2186810A1
EP2186810A1 EP08168104A EP08168104A EP2186810A1 EP 2186810 A1 EP2186810 A1 EP 2186810A1 EP 08168104 A EP08168104 A EP 08168104A EP 08168104 A EP08168104 A EP 08168104A EP 2186810 A1 EP2186810 A1 EP 2186810A1
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European Patent Office
Prior art keywords
het
alkyloxy
diyl
ylc
derivatives
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Withdrawn
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EP08168104A
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German (de)
English (en)
Inventor
Chi-Hung Nguyen
Myriam Rouchon Dagois
Aurore Guedin-Baurepaire
David Monchaud
Marie-Paule Teulade-Fichou
Jean-François RIOU
Jean-Louis Mergny
David Grierson
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Centre National de la Recherche Scientifique CNRS
Institut National de la Sante et de la Recherche Medicale INSERM
Institut Curie
Museum National dHistoire Naturelle
Original Assignee
Centre National de la Recherche Scientifique CNRS
Institut National de la Sante et de la Recherche Medicale INSERM
Institut Curie
Museum National dHistoire Naturelle
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Application filed by Centre National de la Recherche Scientifique CNRS, Institut National de la Sante et de la Recherche Medicale INSERM, Institut Curie, Museum National dHistoire Naturelle filed Critical Centre National de la Recherche Scientifique CNRS
Priority to EP08168104A priority Critical patent/EP2186810A1/fr
Priority to PCT/IB2009/054856 priority patent/WO2010049915A1/fr
Priority to CN200980143020.1A priority patent/CN102203088B/zh
Priority to ES09756849T priority patent/ES2432818T3/es
Priority to JP2011533915A priority patent/JP5636369B2/ja
Priority to US13/124,136 priority patent/US20110201648A1/en
Priority to EP09756849.7A priority patent/EP2340249B1/fr
Priority to CA2740558A priority patent/CA2740558A1/fr
Publication of EP2186810A1 publication Critical patent/EP2186810A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/14—Heterocyclic carbon compound [i.e., O, S, N, Se, Te, as only ring hetero atom]
    • Y10T436/142222—Hetero-O [e.g., ascorbic acid, etc.]
    • Y10T436/143333—Saccharide [e.g., DNA, etc.]

Definitions

  • the present invention relates to poly-heteroaryl derivatives that specifically bind and stabilise quadruplex DNA. It also relates to the synthesis thereof and their biological applications.
  • G-quadruplex DNA is currently considered as a structural element able to regulate the function of G-rich sequences.
  • many lines of evidence suggest that formation of this peculiar DNA structure at telomeres or in specific gene promoters in a variety of human oncogenes, including c-Myc, Bcl-2, VEGF, Hif-1a, Ret, c-Kit, PDGF-A, KRAS and c-Myb (1) may inhibit cancer cell proliferation.
  • Telomeric DNA of human cells comprises tandem repeats of sequence 5'-TTAGGG-3', which terminates on their 3' side in a single-stranded overhang that was demonstrated to fold into G-quadruplex in vitro.
  • the formation of such quadruplex-structure in vivo is hypothesized to lead to the displacement of protective proteins normally associated with telomeres (shelterin complex), therefore disrupting telomere structure leading to genomic instability.
  • telomestatin a naturally-occurring macrocycle (isolated from Streptomyces anulatus 3533-SV4) comprised of five oxazole rings, two methyl oxazole rings and a thiazoline ring.
  • IC 50-POT1 500 nM
  • GFP-POT1 GFP-POT1 from telomeres in tumor cells
  • telomestatin shows the exceptional properties of telomestatin. Additionally, none of these compounds, including telomestatin itself, have been investigated for their fluorescence properties. Given the chemical instability, the poor water-solubility and in particular, the arduous synthesis of telomestatin, its large-scale therapeutic use is questionable.
  • An object of the present invention is then to provide, as new products, such non-macrocyclic polyheteroaryl derivatives.
  • the invention taking advantage of the quadruplex-interacting properties of said compounds, further relates to the use of said derivatives as quadruplex-specific probes.
  • the invention provides pharmaceutical compositions containing said derivatives as active principles and also relates to the use of said derivatives in the manufacture of drugs useful for the treatment of patients suffering from genetic disorders, for example cancer, or infectious diseases such as malaria.
  • the invention also relates to a method for treating cancer or infections diseases comprising administering an efficient amount of said derivatives to a patient in need thereof
  • the polyheteroaryl derivatives of the invention are penta-, hexa-, hepta-, octa-, nona- and deca-heteroaryl (abbreviated hereafter as penta- to deca-heteroaryl)structurally characterized by a combination of heterocycle 1 (Het-1) a and/or heterocycle 2 (Het-2) b and/ or heterocycle 3 (Het-3) c and/or heterocycle 4 (Het-4) d of formulae I, II, III and IV respectively, the N-oxides, the pharmaceutically acceptable addition salts, wherein
  • Het-1 is linked to two Het-2.
  • Het-1 is a pyridyl and Het-4 is an oxazolyl, substituted by a pyridyl or a pyridyl-oxazolyl.
  • Het-2 is linked to two Het-1.
  • Het-2 is an oxazolyl and Het-1 is a pyridyl oxazolyl.
  • the derivatives of the invention specifically bind and stabilise quadruplex DNA and therefore are of great interest as quadruplex-specific probes.
  • the invention thus relates to the use of the above defined derivatives as drugs.
  • compositions comprising an effective amount of at least one derivative such as above defined in combination with a pharmaceutically acceptable carrier.
  • compositions are optionally in association with other active principles.
  • compositions are advantageously under forms suitable for an administration by the oral or parenteral route.
  • Forms appropriate for an oral administration comprise tablets, pills.
  • compositions are under the form of solutions.
  • compositions are particularly useful to treat cancer and infectious diseases such as malaria.
  • an effective daily amount of active principle in the compositions will be from 0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10 mg/kg body weight.
  • the invention also covers a method for making the above defined derivatives.
  • the following examples are intended to illustrate the present invention.
  • the compounds can also obtained by other processes known by the man skilled in the art.
  • the starting materials used 2,6-pyridine dicarboxaldehyde, 6-bromopyridine-2-carbaldehyde, p -toluenesulfonylmethyl isocyanide (TosMIC) and 2-pyridylzinc-bromide, are commercially available.
  • the intermediate 1 (0.1 g ; 0.5 mmol) and TMEDA (0.2 mL ; 1.0 mmol) are dissolved in 5 mL of anhydrous THF and cooled at -78°C.
  • a solution of LiHMDS 1M in THF (1.0 mL ; 1.0 mmol) was added dropwise and stirred during 30 minutes at -78°C and one hour at -40°C.
  • the mixture was cooled again at -78°C and 1,2-diiodoethane (0.5 g ; 1.9 mmol) was added.
  • Method 1 A mixture of intermediate 2 (65 mg ; 0.14 mmol), 2-pyridylzinc-bromide (1.2 mL ; 0.60 mmol) and Pd(PPh 3 ) 4 (12 mg ; 0.01 mmol) were heated at reflux in 2 mL of anhydrous THF during 4 hours. Water was added and the mixture was extracted with ethyl acetate (3x10 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo.
  • Method 2 A mixture of intermediate 1 (0.1 g ; 0.5 mmol), 2-bromopyridine (91 ⁇ L ; 0.9 mmol), palladium diacetate (11 mg ; 0.05 mmol ; 10 mol%), PCy 3 .HBF 4 (35 mg ; 0.1 mmol ; 20 mol%), copper (I) iodide (0.18 g ; 0.9 mmol), cesium carbonate (0.61 mg ; 1.88 mmol) and 1.3 mL of anhydrous toluene were submitted under microwave irradiation conditions (130°C, 150W) during 4 hours. The residue was purified by flash chromatography (SiO 2 , dichloromethane-ethanol, 95-5) to give the compound 1 (8 mg, 33%) which is identically with than that described in method 1 above.
  • 6-Bromopyridine-2-carbaldehyde (4.0 g ; 21.5 mmol), TosMIC (4.2 g ; 21.5 mmol) and potassium carbonate (6.0 g ; 43.4 mmol) were heated at reflux during 3 hours in 75 mL of methanol. The solvent was evaporated in vacuo and the residue was poured into brine solution and extracted with dichloromethane (4x100 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo.
  • UV-vis properties of pyridine-based polyheteroaromatic compounds detailed in this study enable the determination of their solubility in various conditions (DMSO, H 2 O and cacodylate buffers (10mM sodium cacodylate + 100mM NaCl (for Caco.Na) or KCl (for Caco.K)): the simplest method for this is to measure the absorption spectra of compound 3 at various concentrations (from 0 to 32 ⁇ M); solubility of compound 3 is thus evaluated through the reporting of its absorbance at a given wavelength (herein 338nm (A 338 ) as a function of the concentration of compound 3 and applying the Beer-Lambert law. The results are given in Fig.1 .
  • Stabilization, and so interaction, of compounds with quadruplex-structure is monitored via FRET-melting assay, in a version that also enables the determination of the quadruplex- over duplex-DNA selectivity as well as the intra-quadruplex selectivity (17).
  • FRET assay is performed with oligonucleotides that mimic the human or plasmodium telomeric sequences, and equipped with FRET partners at each extremities: F21T ( FAM- G 3 [T 2 AG 3 ] 3 - Tamra ,) FPf1T (FAM-G 3 [T 3 AG 3 ] 3 - Tamra ) and FPf8T ( FAM -G 3 [T 2 CAG 3 ] 3 - Tamra ) with FAM: 6-carboxyfluorescein and Tamra : 6-carboxy-tetramethylrhodamine). Measurements were made with excitation at 492nm and detection at 516nm.
  • Fluorescence melting are carried out with 0.2 ⁇ M of F21T in a buffer containing 10mM lithium cacodylate pH 7.2 and 100mM NaCl; the melting of the G-quadruplex was monitored alone and in the presence of 1 ⁇ M of compound 3 without or with excess (1, 3 and 10 ⁇ M) of duplex-DNA competitor ds26 (a 26 base-pair duplex-DNA comprised of the self complementary sequence [5'-CAATCGGATCGAATTCGATCCGATTG-3']). The results are given on Fig. 4
  • Fluorescence melting experiments are carried out with 0.2 ⁇ M of F21T in a buffer containing 10mM lithium cacodylate pH 7.2 and 100mM NaCl; the melting of the G-quadruplex was monitored alone and in the presence of 1 ⁇ M of compound 3 without or with excess (1, 3 and 10 ⁇ M) of quadruplex-DNA competitors, either TG5T ([(5'-TG 5 T-3') 4 ], a tetramolecular quadruplex-DNA used in previous study (21) or c-myc ([5'-GAGGGTGGGGAGGGTGGGGAAG-3'], a sequence present in the promoter region of the oncogene c-myc, highly suspected to fold into an intramolecular quadruplex-structure (22-25). The results are given on Fig. 5A -Fig.5B .
  • Pyridine-based polyheteroaromatic compounds detailed in this study are characterized by a strong fluorescence.
  • the quantum yield is not affected by the nature of the solvent they are used in, from pure organic (e.g. DMSO) to physiological conditions (e.g. buffer: 10mM sodium cacodylate + 100mM KCl, pH 7.2, see Table).
  • physiological conditions e.g. buffer: 10mM sodium cacodylate + 100mM KCl, pH 7.2, see Table.
  • the modification of the fluorescence properties of studied compounds upon interaction with DNA enables to compare their apparent binding affinity for several quadruplexes of biological relevance (27).
  • DCM Water Quantum yield 0.5 0.5 s.d. 2.17% 2,89% NB: the quantum yields (and standard deviations (s.d.)) of compound 3 were measured in CH 2 Cl 2 (DCM) and water, with anthracene in ethanol as reference.
  • the quadruplex-DNA used herein is 22AG: it results from the folding of a 22nt oligonucleotide that mimics the human telomeric sequence: 22AG is [5'-AG 3 (T 2 AG 3 ) 3 -3'].
  • Quadruplex-structure from 22AG is prepared by heating the corresponding oligonucleotide at 90°C for 5min in a 10mM sodium cacodylate buffer pH 7.2, 100 mM NaCl (for 22AG Na) or KCl (for 22AG K) and cooling in ice to favor the intramolecular folding by kinetic trapping. Concentrations are determined by UV-Vis measurements (after thermal denaturation, 5min at 85°C) at 260nm before use. (see F ig 7A and Fig.7B ).
  • duplex-structure is prepared by heating the two corresponding complementary strands at 90°C for 5min in a 10mM sodium cacodylate buffer pH 7.3, 100 mM KCl followed by a slow cooling over 6hrs.
  • the intra-quadruplex selectivity is evaluated through fluorescence titrations by comparison of experiments carried out with 22AG (see above) and with two other quadruplex-structures: c-myc and c-kit2.
  • the formation of these two quadruplex-DNAs is currently highly suspected in the promoter region of c-myc (see above) and c-kit (22; 29 and 30)oncogenes.
  • c-myc [5'-TGAGGGTGGGTAGGGTGGGTAA-3'] and c-kit2 : [(5'-CGGGCGGGCGCGAGGGAGGGG-3'];
  • Quadruplex-structures are prepared by heating the corresponding oligonucleotide at 90°C for 5min in a 10mM sodium cacodylate buffer pH 7.2, 100 mM KCl and cooling in ice to favor the intramolecular folding by kinetic trapping. Concentrations are determined by UV-Vis measurements (after thermal denaturation, 5min at 85°C) at 260nm before use. The results are given on Fig.9A and Fig.9B .
  • Circular dichroism enables a deep study of the modification of the DNA structure upon the binding of a ligand; it thus reflects the affinity of the ligand to its target, and can also provide insight into its binding mode ( Paramasivan et al, Methods, 2007, 43, 324 ).
  • the quadruplex-DNA used herein is 22AG (see above), annealed both in a 10mM sodium cacodylate buffer pH 7.2, 100 mM NaCl (for 22AG Na) or KCl (for 22AG K). To a 3 ⁇ M solution of 22AG in both buffers is added an excess of compound 3 (30 ⁇ M, 10 equiv.). Th results are given in Fig.11 .
  • the interaction of compound 3 with quadruplexes is monitored as a function of time: it results in a modification of the amplitude of the CD signal of 22AG Na (left, especially at 263nm), while it reorganises completely the structure of 22AG K (right, especially at 263nm).
  • the intra-quadruplex selectivity is evaluated through CD by comparison of experiments carried out with 22AG (see above) and with two other quadruplex-structures: c-myc and c-kit2 (see above). The results are given on Fig. 11A and Fig.11B .
  • cacodylate buffer 10mM sodium cacodylate + 100mM KCl
  • telomeric 22AG oligonucleotide (see above). 22AG was labeled at the 5' end with [ ⁇ - 32 P]-ATP using T4 polynucletide kinase. Purified recombinant hPOT1 was produced in a baculovirus expression system.
  • the POT1/22AG binding assay was performed in a total volume of 10 ⁇ l containing 50 mM HEPES, pH 7.9, 100 mM NaCl, 0.1 mM EDTA, 4% w/v sucrose, 2% v/v glycerol, 0.1 mg/ml BSA, 0.02% w/v bromophenol blue, 30 nM hPOT1, 20 nM [ ⁇ - 32 P]-22AG.
  • Different concentrations of compound 3 (10, 1, 0.1 and 0.01 ⁇ M) were added with hPOT1 to the solution and the mixture was incubated at room temperature for 30 min. Each individual sample was separated by electroporesis on 1% agarose gel in 0.5X Tris-Borate-EDTA buffer.
  • the gel was run at 80V for35 min, dried on whatman DE81 paper and radiaoactivity visualized by a phosphorimager (Typhoon 9210, Amersham). Analysis of the data was carried out by ImageQuant software (Amersham) and results were expressed as a percentage of the POT1-22AG complex obtained in the untreated control (defined as 100%) (see Fig. 14 ).
  • the HT1080 human fibrosarcoma cell line stably transfected with pEGFP-POT1 vector has been previously described (32) and U20S human osteosarcoma was from American Type Culture Collection (Rockville, USA).
  • Cells were grown in Dublecco's modified Eagles's medium (Invitrogen) supplemented with 10% v/v fetal bovine serum and with 400 ⁇ g/ml geneticin for HT1080GFP-POT1.
  • Cells were plated in 6-wells culture plates on day 0 at 4.5 x10 4 cells/well in the presence of different concentrations of compound 3 (10, 3, 1, 0.3 and 0.1 ⁇ M), each concentration in duplicate, and cultured for further 72 hours.

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EP08168104A 2008-10-31 2008-10-31 Dérivés de poly-hétéroaryle pour le traitement de cancer Withdrawn EP2186810A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
EP08168104A EP2186810A1 (fr) 2008-10-31 2008-10-31 Dérivés de poly-hétéroaryle pour le traitement de cancer
PCT/IB2009/054856 WO2010049915A1 (fr) 2008-10-31 2009-11-02 Dérivés de poly-hétéroaryle pour le traitement du cancer
CN200980143020.1A CN102203088B (zh) 2008-10-31 2009-11-02 用于癌症治疗的聚杂芳基衍生物
ES09756849T ES2432818T3 (es) 2008-10-31 2009-11-02 Derivados de poli-heteroarilo para el tratamiento del cáncer
JP2011533915A JP5636369B2 (ja) 2008-10-31 2009-11-02 癌の処置用のポリ−ヘテロアリール誘導体
US13/124,136 US20110201648A1 (en) 2008-10-31 2009-11-02 Poly-heteroaryl derivatives for the treatment of cancer
EP09756849.7A EP2340249B1 (fr) 2008-10-31 2009-11-02 Dérivés de poly-hétéroaryle pour le traitement du cancer
CA2740558A CA2740558A1 (fr) 2008-10-31 2009-11-02 Derives de poly-heteroaryle pour le traitement du cancer

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EP08168104A EP2186810A1 (fr) 2008-10-31 2008-10-31 Dérivés de poly-hétéroaryle pour le traitement de cancer

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EP09756849.7A Not-in-force EP2340249B1 (fr) 2008-10-31 2009-11-02 Dérivés de poly-hétéroaryle pour le traitement du cancer

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US (1) US20110201648A1 (fr)
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JP (1) JP5636369B2 (fr)
CN (1) CN102203088B (fr)
CA (1) CA2740558A1 (fr)
ES (1) ES2432818T3 (fr)
WO (1) WO2010049915A1 (fr)

Cited By (2)

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Publication number Priority date Publication date Assignee Title
EP2496704A1 (fr) * 2009-11-05 2012-09-12 Rutgers, The State University of New Jersey Composés thérapeutiques
US8993607B2 (en) 2007-08-02 2015-03-31 Rutgers, The State University Of New Jersey Therapeutic compounds

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WO2014163173A1 (fr) * 2013-04-04 2014-10-09 Jnc株式会社 Matériau de transport d'électrons et dispositif électroluminescent organique l'utilisant
US20210024455A1 (en) * 2018-03-20 2021-01-28 Hiroshima University Compound which inhibits telomere-binding protein, and telomere-binding protein inhibitor containing same
CN112300148B (zh) * 2020-11-19 2022-04-01 安徽医科大学 一种硝酸酯类no供体型三吡啶联噁唑类化合物及其制备方法和应用

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WO2007119461A1 (fr) * 2006-03-24 2007-10-25 Hodogaya Chemical Co., Ltd. Composé avec une structure cyclique thiadiazole substituée par un groupe pyridyle, et dispositif électroluminescent organique
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8993607B2 (en) 2007-08-02 2015-03-31 Rutgers, The State University Of New Jersey Therapeutic compounds
EP2496704A1 (fr) * 2009-11-05 2012-09-12 Rutgers, The State University of New Jersey Composés thérapeutiques
EP2496704A4 (fr) * 2009-11-05 2013-05-01 Univ Rutgers Composés thérapeutiques
US8796300B2 (en) 2009-11-05 2014-08-05 Rutgers, The State University Of New Jersey Therapeutic compounds

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CA2740558A1 (fr) 2010-05-06
EP2340249B1 (fr) 2013-09-11
CN102203088B (zh) 2014-04-30
WO2010049915A1 (fr) 2010-05-06
ES2432818T3 (es) 2013-12-05
US20110201648A1 (en) 2011-08-18
EP2340249A1 (fr) 2011-07-06
JP2012507504A (ja) 2012-03-29
CN102203088A (zh) 2011-09-28
JP5636369B2 (ja) 2014-12-03

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